Doxorubicin induces cardiomyocyte pyroptosis via the TINCR-mediated posttranscriptional stabilization of NLR family pyrin domain containing 3

Meng, Lingjun; Lin, Hui; Zhang, Jie; Lin, Na; Sun, Zhenzhu; Gao, Feidan; Luo, Hongwei; Ni, Tingjuan; Luo, Wenqiang; Chi, Jufang; Guo, Hangyuan

doi:10.1016/j.yjmcc.2019.08.009

Cited by 95 publications

(58 citation statements)

References 43 publications

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“…DRP1/NOX signaling was activated to cause mitochondrial damage, which involved in DOX-induced pyrotosis (Zeng et al, 2020). Moreover, upregulated lncRNA TINCR recruited IGF2BP1 to enhance the NLRP3 expression that mediated Dox-induced pyrotosis (Meng et al, 2019). However, embryonic stem cells-derived exosomes and Heat-shock Protein 22 can reverse the Dox-induced cardiomyocytes pyrotosis via inhibiting TLR4/NLRP3/caspase-1 signaling (Tavakoli et al, 2019;Lan et al, 2020).…”

Section: Pyroptosismentioning

confidence: 99%

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

Wei

Zhang

et al. 2020

Front. Cell Dev. Biol.

108

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Homeostatic regulation of cardiomyocytes plays a crucial role in maintaining the normal physiological activity of cardiac tissue. Severe cardiotoxicity results in cardiac diseases including but not limited to arrhythmia, myocardial infarction and myocardial hypertrophy. Drug-induced cardiotoxicity limits or forbids further use of the implicated drugs. Such drugs that are currently available in the clinic include anti-tumor drugs (doxorubicin, cisplatin, trastuzumab, etc.), antidiabetic drugs (rosiglitazone and pioglitazone), and an antiviral drug (zidovudine). This review focused on cardiomyocyte death forms and related mechanisms underlying clinical drug-induced cardiotoxicity, including apoptosis, autophagy, necrosis, necroptosis, pryoptosis, and ferroptosis. The key proteins involved in cardiomyocyte death signaling were discussed and evaluated, aiming to provide a theoretical basis and target for the prevention and treatment of drug-induced cardiotoxicity in the clinical practice.

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Section: Pyroptosismentioning

confidence: 99%

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

Wei

Zhang

et al. 2020

Front. Cell Dev. Biol.

108

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“…Doxorubicin treatment significantly increased cardiac expression of TLR4, NLRP3, caspase-1, IL-1β, IL-18, TNF-α, and cell signaling proteins (MyD88, p-P38, and p-JNK) in mice (Singla et al, 2019). It has been reported that terminal differentiation-induced non-coding RNA (lncRNA TINCR) could attenuate cardiac hypertrophy by epigenetically silencing CaMKII and insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) could participate in the modification of mRNA stability (Shao et al, 2017;Meng et al, 2019). Meng et al (2019) first demonstrated that lncRNA TINCR acted as a critical upstream regulatory factor in doxorubicininduced cardiomyocyte NLRP3 inflammasome activation and pyroptosis in a TINCR/IGF2BP1/NLRP3-dependent manner.…”

Section: Doxorubicin-induced Cardiotoxicitymentioning

confidence: 99%

“…It has been reported that terminal differentiation-induced non-coding RNA (lncRNA TINCR) could attenuate cardiac hypertrophy by epigenetically silencing CaMKII and insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) could participate in the modification of mRNA stability (Shao et al, 2017;Meng et al, 2019). Meng et al (2019) first demonstrated that lncRNA TINCR acted as a critical upstream regulatory factor in doxorubicininduced cardiomyocyte NLRP3 inflammasome activation and pyroptosis in a TINCR/IGF2BP1/NLRP3-dependent manner. Doxorubicin increased TINCR expression by inducing H3K27 acetylation at the promoter region of TINCR gene and activating transcription in cardiomyocytes.…”

Section: Doxorubicin-induced Cardiotoxicitymentioning

confidence: 99%

NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity

Wei

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Drug-induced toxicity, which impairs human organ function, is a serious problem during drug development that hinders the clinical use of many marketed drugs, and the underlying mechanisms are complicated. As a sensor of infections and external stimuli, nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a key role in the pathological process of various diseases. In this review, we specifically focused on the role of NLRP3 inflammasome in drug-induced diverse organ toxicities, especially the hepatotoxicity, nephrotoxicity, and cardiotoxicity. NLRP3 inflammasome is involved in the initiation and deterioration of drug-induced toxicity through multiple signaling pathways. Therapeutic strategies via inhibiting NLRP3 inflammasome for drug-induced toxicity have made significant progress, especially in the protective effects of the phytochemicals. Growing evidence collected in this review indicates that NLRP3 is a promising therapeutic target for drug-induced toxicity.

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“…The permeability of pyroptotic cell membranes can also be determined through the release of the cytoplasmic enzyme lactose dehydrogenase (LDH) (Ding et al, 2019;Gu et al, 2019). Recent studies showed that pyroptosis also occurs in cardiomyocytes (Pan et al, 2018;Meng et al, 2019;Wang X. et al, 2019). In our previous study, we showed that NLRP3 inflammasomeinduced caspase-1 activation promotes cardiomyocyte pyroptosis in DCM.…”

Section: Introductionmentioning

confidence: 99%

Chemerin/CMKLR1 Axis Promotes Inflammation and Pyroptosis by Activating NLRP3 Inflammasome in Diabetic Cardiomyopathy Rat

et al. 2020

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Chemerin and its receptor CMKLR1 (a G-protein-coupled receptor) are inducers of inflammation, and play an important role in diabetic cardiomyopathy (DCM). In this study, we investigated the role of the chemerin/CMKLR1 axis in mediating inflammation and cell death in DCM. Sprague-Dawley rats, treated with a high-fat diet and low-dose of streptozotocin, were used as a DCM model. CMKLR1 expression was knocked down by siRNA (CMKLR1-siRNA) to evaluate the role of CMKLR1 in DCM. Chemerintreated H9c2 cells were used to investigate the factors acting downstream of the chemerin/CMKLR1 axis. LDH release and EthD-III staining were used to measure the ratio of cell death in vitro. CMKLR1-siRNA and siRNA against nucleotide-binding oligomerization domain-like receptors 3 (NLRP3-siRNA) were used to explore the mechanism underlying chemerin-induced inflammation and cell death. The results showed that the expression of chemerin, CMKLR1, NLRP3, pro-caspase-1, activated caspase-1, and mature IL-1β was increased in the DCM model rat. Myocardium of DCM model rats exhibited fibrosis, hypertrophy, a disorganized ultrastructure, and impaired function. Pyroptosis was observed in vivo and in vitro. Silencing of CMKLR1 in vivo attenuated the expression of NLRP3 and activated caspase-1 and IL-1β. CMKLR1-siRNA treatment attenuated cardiac inflammation, fibrosis, hypertrophy, and pyroptosis, and improved cardiac function in vivo. Silencing of either CMKLR1 or NLRP3 suppressed the levels of activated caspase-1, IL-1β, and pyroptosis; however, silencing of both CMKLR1 and NLRP3 further decreased the levels of mature IL-1β and pyroptosis. Overall, the results showed that the chemerin/CMKLR1 axis contributed to the development of DCM and that the NLRP3 inflammasome mediated the chemerin/CMLR1-induced inflammation and pyroptosis. These data indicate that silencing of the CMKLR1 gene might exert a protective effect against DCM.

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Doxorubicin induces cardiomyocyte pyroptosis via the TINCR-mediated posttranscriptional stabilization of NLR family pyrin domain containing 3

Cited by 95 publications

References 43 publications

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity

NLRP3 Inflammasome: A Promising Therapeutic Target for Drug-Induced Toxicity

Chemerin/CMKLR1 Axis Promotes Inflammation and Pyroptosis by Activating NLRP3 Inflammasome in Diabetic Cardiomyopathy Rat

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